In 2003, available pharmacotherapy for mood disorders was based almost entirely on observations from the 1950s and 1960s that agents that enhance monoamine transmitter function are effective antidepressants. Preclinical studies show that chronic administration of all effective antidepressants increases the efficiency of post-synaptic 5-HT transmission. Many antidepressants also modify nor-adrenergic function in the central nervous system. For the majority of antidepressants, these long-term changes in serotonergic and/or noradrenergic function result from direct antagonism of serotonin and/ or norepinephrine transporters (also termed "uptake sites"). Pharmacotherapy that is highly selective for one transporter over another has been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may be associated with additional adverse events. Nevertheless, the rationale is in place to suggest that antidepressants that block both the serotonin and norepinephrine transporters might provide better efficacy, which can only be determined by empirical testing.